Growth hormone (GH) or somatotropin is secreted by the pituitary gland. Its activity is fundamental for the linear growth of a young organism but also for the maintenance of the integrity at its adult state. GH acts directly or indirectly on the peripheral organs by stimulating the synthesis of growth factors (insulin-like growth factor-I or IGF-I) or of their receptors (epidermal growth factor or EGF). The direct action of GH is of the type referred to as anti-insulinic, which favors the lipolysis at the level of adipose tissues. Through its action on IGF-I (somatomedin C) synthesis and secretion, GH stimulates the growth of cartilage and the bones (structural growth), protein synthesis and cellular proliferation in multiple peripheral organs, including muscles and skin. In adults, GH participates in the maintenance of a protein anabolism state and plays a primary role in the tissue regeneration phenomenon after a trauma.
The secretion of GH by the pituitary gland is principally controlled by two hypothalamic peptides, somatostatin and growth hormone releasing factor (GRF; also known as GH-releasing hormone or GHRH). Somatostatin inhibits its secretion, whereas GRF stimulates it. Human GRF is a 44 amino acid peptide. A peptide consisting of the first 29 amino acids of human GRF (hGRF(1-29); sermorelin) retains the biological activity of the full-length peptide (Lance, V. A. et al., Biochemical and Biophysical Research Communications 1984, 119: 265-272) and has been used clinically for the treatment of GH deficiency in children (Thorner, M. et al., Journal of Clinical Endocrinology and Metabolism 1996, 81: 1189-1196). More recently, the potential of GRF to reverse the age-related decline in the function of the somatotrophic GH-insulin-like growth factor (IGF)-I axis has been evaluated (Khorram, O. et al., Clinical Obstetrics and Gynecology 2001, 44: 893-901).
Among all known GRF molecules, GRF analogs containing a hydrophobic tail as defined in the present application are modified versions or analogs of human GRF that have been shown to have higher proteolytic stability in biological milieu and as a result, these analogs were shown to display longer duration of action resulting in enhanced growth hormone secretion and insulin like growth factor-1 synthesis (U.S. Pat. Nos. 5,861,379 and 5,939,386). Due to their superior plasma stability and pharmacological properties compared to the native GRF (1-44) amide, these GRF analogs were shown to confer therapeutic efficacy in several medical conditions, e.g., wasting associated with cystic fibrosis and COPD (International Application No. WO 05/037307), recovery after hip fracture, frailty in elderly population, enhancing immune response and HIV-associated lipodystrophy (U.S. Pat. No. 7,316,997).
In practical terms, it is very important to conserve the physical and chemical integrity of a peptide compound of pharmaceutical interest during its manufacturing process, subsequent handling, storage, and patient use. Loss of biological efficacy and potency has been associated with changes in physical (e.g., aggregation, denaturation, changes in secondary and higher order structures) and chemical (e.g., oxidation, deamidation, isomerization of individual amino acids) integrity.
Some denaturation problems are specific to certain amino acids or certain amino acid sequences such as proteolysis, enzymatic degradation, oxidation, pH-related denaturation, etc.
Therefore, there is a need to provide improved formulations of GRF molecules as well so as to improve retention of its bioactivity after long-term storage.